At least seven different receptor classes mediate the physiological activities attributed to involvement of the neurotransmitter serotonin (5-hydroxytryptamine, abbreviated 5-HT). They are designated as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 according to an internationally recognized classification system. Most of these classes also include other receptor subtypes that can be differentiated; for example, the 5-HT1 class includes receptors that can be subdivided into at least five subclasses, namely 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D and 5-HT1E (Martin Boess; Neuropharmacology 33:275-317 (1994)).
The properties, function and pharmacology of these receptor subtypes have been summarized, e.g., by (a) G. A. Kennet, Serotonin Receptors and their Function,” TOCRIS Review (http://www.tocris.com/serotonin.htm), published May 1997; (b) S. J. Peroutka, 1994, “Molecular Biology of Serotonin (5-HT) Receptors, Synapse 18, 241-260 and Current Drug Targets—CNS & Neurological Disorders 2004, 3, No. 1.
The 5-HT5 class was described for the first time by Plassat et al., The EMBO Journal, vol. 11, no. 13, pp. 4779-4786 (1992). A distinction is made between 5-HT5A and 5-HT5B receptors (Erlander et al., Proc. Natl. Acad. Sci. USA 90:3452-3456 (1993)). Although there are only minor sequence homologies between 5-HT5 and other 5-HT receptors, the pharmacological profile of these receptors is definitely different.
5-HT5 receptors have been localized with the help of the techniques of molecular biology in the olfactory bulb, the hippocampus, the cortex, the cerebral ventricles, the corpus callosum and the cerebellum. By using immunohistochemical methods, it has been demonstrated that 5-HT5 receptors are expressed by neurons in various areas of the brain (Oliver et al., Brain Res 2000, 867, 131-142; Pasqualetti et al., Mol Brain Res 1998, 56, 1-8). These 5-HT5 receptors can modulate important brain functions either directly or indirectly, but they may also be involved in mechanisms that play a role in neuropathological, neurodegenerative and neuropsychiatric diseases. 5-HT5 receptors have also been localized in astrocytes (Carson et al., GLIA 17:317-326 (1996)). Astrocytes are situated directly on the basal membrane of cerebral capillaries of the blood-brain barrier, and an abnormal astrocyte-endothelium structure is associated with a loss of blood-brain barrier. The precise function of astrocytes is unclear. They appear to execute transport tasks and connective functions. Reactive astrocytes have been observed in conjunction with reactive gliosis in a number of pathological cerebral changes and neuropsychiatric disorders. These astrocytes undergo a change in morphology as a result of brain injuries. The protein expression pattern changes and growth factors are produced. In vitro studies on cultured astrocytes show 5-HT5 receptor-mediated responses. For this reason, it is assumed first that 5-HT5 receptors are involved in recovery processes in the brain after a trauma, but on the other hand, the possibility cannot be ruled out that they play a role in the damage itself or may even contribute toward increasing the injury.
Diseases of the central nervous system today affect large portions of the population, and the number of patients is steadily increasing especially due to the growing elderly population. Neuropathological conditions such as cerebral ischemia, cerebral vascular accident, epilepsy and seizures in general, chronic schizophrenia, other psychotic diseases, depression, anxiety states, bipolar disorder, dementia, especially Alzheimer's disease, demyelinizing diseases, in particular multiple sclerosis and brain tumors lead to damage to the brain and the neural deficiencies associated with such damage. Therapeutic treatments of the neurodegenerative and neuropsychiatric disorders mentioned here have so far been directed at various membrane receptors with the goal of compensating for deficiencies in neurotransmission processes. Although neuroprotective effects have been achieved with various serotonergic compounds in animal models for neuropathological states such as ischemia, cerebral stroke and excitotoxicity, positive effects on mood disorders such as depression or anxiety have also been observed to some extent. Examples that can be mentioned here include 5-HT1A agonists such as buspirone or the compound 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), which is characterized as a selective 5-HT1A receptor ligand. However, these active ingredients relieve the neurological deficiencies described here only to a limited extent, but at the present time there is still no effective treatment for these diseases.
Migraines are another neuropathological disease affecting large portions of the population. Migraines are in most cases manifested as recurring headaches, which have been estimated as affecting eight million people, i.e., 3-5% of all children, 7% of all men and 14% of all women. Although a genetic predisposition has been suggested, the causes appear to be varied (H. C. Diener et al., Arzneimitteltherapie 15:387-394 (1997)). Two hypotheses are dominant. The vascular theory, which has been known for a long time, suggests a dilatation process of the internal and external cerebrovascular system as the cause. The neurogenic theory is based on secretion of vasoactive neurotransmitters, mainly neuropeptides, such as substance P and neurokinin from axons of the vasculature due to stimulation of certain ganglia innervating the cerebral tissue, leading to inflammatory reactions and thus to pain.
There is not yet a causal therapy for treatment of migraines. Two different treatment methods are presently being used: the first is a prophylactic treatment for prevention of recurring migraine attacks and the second is a symptomatic treatment for suppression of acute symptoms once an attack has occurred. Migraine-specific active ingredients such as Sanmigran®, Nocerton®, Desernil® and Vidora® are used prophylactically, but active ingredients normally used for other indications such as β-blockers, antiemetic active ingredients such as Sibelium®, antidepressants such as Laroxyl® or antiepileptic agents such as Depakin® are also administered. For acute therapy, analgesics such as aspirin, paracetamol or Optalidon®, NSAIDs (non-steroidal anti-inflammatory drugs) such as Cebutid®, Voltaren®, Brufen®, Ponstyl®, Profenid®, Apranx® and Naprosyn® are administered to relieve the pain and inflammation, while ergot alkaloids such as ergotamine, dihydroergotamine, which can trigger vasoconstriction, or substances of the triptan family, such as sumatriptan, Naramig® and AscoTop®, which have a high affinity for 5-HT1D receptors, are also administered. The latter substances act as agonists and block vasodilation.
However, the active ingredients mentioned above are not optimal for treatment of migraines. Nonopioid analgesics often have side effects. The complex mechanism of action of the ergot alkaloids leads to side effects such as hypertension or even gangrene due to the strong peripheral vasoconstriction effect. Compounds belonging to the triptan family are also not completely satisfactory (V. Pfaffenrath, Münch. Med. Wschr. 625-626 (1998)).
5-HT5 receptors have a high affinity for various antidepressants and antipsychotics. Previous studies indicate a role of 5-HT5 receptors in the following syndromes:
Psychosis, depression, chronic schizophrenia, other psychotic diseases, anxiety states, bipolar disorders, dementia, especially Alzheimer's disease, demyelinizing diseases, in particular multiple sclerosis, ischemia, cerebral stroke and migraines.
The use of 5-HT5 receptor ligands in general for treatment of migraines and other cerebrovascular diseases is described in WO00/041472 and their use for treatment of neurodegenerative and neuropsychiatric diseases is described in WO00/041696.
There is therefore a demand for substances that trigger modulation of the 5-HT5A receptor activity.